Project Summary This application is for a Single-Site Investigator-Initiated Clinical Trial (R61/R33) entitled ?Effects of Interleukin-1 blockade on exercise capacity in patients with recently decompensated systolic heart failure? submitted by Antonio Abbate MD, PhD and Benjamin Van Tassell, PharmD. Heart failure (HF) is a complex clinical syndrome characterized by fatigue and labored breathing upon exertion. Although current treatment options have extended life expectancy, prognosis for HF remains poor and HF is the leading cause of admission among elderly patients in the US. There is an urgent need to develop novel treatments to alleviate symptoms, slow disease progression, and reduce HF hospitalization. A significant correlation exists between declining cardiac function and increasing levels of inflammatory cytokines in HF patients. Among these cytokines, Interleukin-1 (IL-1) is a key mediator of systemic inflammation that becomes elevated in HF patients and may contribute to poor cardiac function. In animal models of HF, IL-1 is sufficient to cause significant depression of cardiac function, impaired cardiac reserve, and worsened cardiac remodeling. In a recent pilot study, 12 weeks treatment with recombinant human IL-1 receptor antagonist (IL-1Ra, anakinra) produced a significant improvement in aerobic exercise performance as measured by peak oxygen consumption (VO2). This proposal will support a randomized, double-blind, phase II clinical trial (n=102) to confirm the effect of IL-1 blockade to improve exercise capacity in HF patients and estimate the potential benefit of IL-1 blockade on HF readmission in patients with recently decompensated heart failure (HF). Eligible patients will be randomized to 24 weeks treatment with anakinra (n=68) or placebo (n=34). Results from this study will be used to optimize the treatment strategy and design a subsequent phase III clinical trial to evaluate long-term morbidity and mortality with IL-1 blockade in HF patients.